Spermatogenesis

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Spermatogenesis
Seminiferous tubule and sperm.jpg
Seminiferous tubule with maturing sperm. H&E stain.
Simplified spermatozoon diagram.svg
A mature human Spermatozoon
Identifiers
MeSH D013091
Anatomical terminology
Normal spermatogenesis, testis biopsy. Normal spermatogenesis, intermed. mag.jpg
Normal spermatogenesis, testis biopsy.
High-power view of a seminiferous tubule with normal spermatogenesis. Normal spermatogenesis, very high mag.jpg
High-power view of a seminiferous tubule with normal spermatogenesis.

Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testicle. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubules. [1] These cells are called spermatogonial stem cells. The mitotic division of these produces two types of cells. Type A cells replenish the stem cells, and type B cells differentiate into primary spermatocytes. The primary spermatocyte divides meiotically (Meiosis I) into two secondary spermatocytes; each secondary spermatocyte divides into two equal haploid spermatids by Meiosis II. The spermatids are transformed into spermatozoa (sperm) by the process of spermiogenesis. These develop into mature spermatozoa, also known as sperm cells. [2] Thus, the primary spermatocyte gives rise to two cells, the secondary spermatocytes, and the two secondary spermatocytes by their subdivision produce four spermatozoa and four haploid cells. [3]

Contents

Spermatozoa are the mature male gametes in many sexually reproducing organisms. Thus, spermatogenesis is the male version of gametogenesis, of which the female equivalent is oogenesis. In mammals it occurs in the seminiferous tubules of the male testes in a stepwise fashion. Spermatogenesis is highly dependent upon optimal conditions for the process to occur correctly, and is essential for sexual reproduction. DNA methylation and histone modification have been implicated in the regulation of this process. [4] It starts during puberty and usually continues uninterrupted until death, although a slight decrease can be discerned in the quantity of produced sperm with increase in age (see Male infertility).

Spermatogenesis starts in the bottom part of seminiferous tubes and, progressively, cells go deeper into tubes and moving along it until mature spermatozoa reaches the lumen, where mature spermatozoa are deposited. The division happens asynchronically; if the tube is cut transversally one could observe different maturation states. A group of cells with different maturation states that are being generated at the same time is called a spermatogenic wave. [5]

Purpose

Spermatogenesis produces mature male gametes, commonly called sperm but more specifically known as spermatozoa, which are able to fertilize the counterpart female gamete, the oocyte, during conception to produce a single-celled individual known as a zygote. This is the cornerstone of sexual reproduction and involves the two gametes both contributing half the normal set of chromosomes (haploid) to result in a chromosomally normal (diploid) zygote.

To preserve the number of chromosomes in the offspring – which differs between species – one of each gamete must have half the usual number of chromosomes present in other body cells. Otherwise, the offspring will have twice the normal number of chromosomes, and serious abnormalities may result. In humans, chromosomal abnormalities arising from incorrect spermatogenesis results in congenital defects and abnormal birth defects (Down syndrome, Klinefelter syndrome) and in most cases, spontaneous abortion of the developing foetus.

Location in humans

Spermatogenesis takes place within several structures of the male reproductive system. The initial stages occur within the testes and progress to the epididymis where the developing gametes mature and are stored until ejaculation. The seminiferous tubules of the testes are the starting point for the process, where spermatogonial stem cells adjacent to the inner tubule wall divide in a centripetal direction—beginning at the walls and proceeding into the innermost part, or lumen—to produce immature sperm. [2] Maturation occurs in the epididymis. The location [Testes/Scrotum] is specifically important as the process of spermatogenesis requires a lower temperature to produce viable sperm, specifically 1°-8 °C lower than normal body temperature of 37 °C (98.6 °F). [6] Clinically, small fluctuations in temperature such as from an athletic support strap, causes no impairment in sperm viability or count. [7]

Duration

For humans, the entire process of spermatogenesis is variously estimated as taking 74 days [8] [9] (according to tritium-labelled biopsies) and approximately 120 days [10] (according to DNA clock measurements). Including the transport on ductal system, it takes 3 months. Testes produce 200 to 300 million spermatozoa daily. [11] However, only about half or 100 million of these become viable sperm. [12]

Stages

The entire process of spermatogenesis can be broken up into several distinct stages, each corresponding to a particular type of cell in humans. In the following table, ploidy, copy number and chromosome/chromatid counts are for one cell, generally prior to DNA synthesis and division (in G1 if applicable). The primary spermatocyte is arrested after DNA synthesis and prior to division.

Cell type ploidy/chromosomes in humanDNA copy number/chromatids in humanProcess entered by cell
spermatogonium (types Ad, Ap and B)diploid (2N) / 462C / 46 spermatocytogenesis (mitosis)
primary spermatocyte diploid (2N) / 464C / 2x46 spermatidogenesis (meiosis I)
two secondary spermatocytes haploid (N) / 232C / 2x23spermatidogenesis (meiosis II)
four spermatids haploid (N) / 23C / 23 spermiogenesis
four functional spermatozoids haploid (N) / 23C / 23spermiation

Spermatocytogenesis

The process of spermatogenesis as the cells progress from primary spermatocytes, to secondary spermatocytes, to spermatids, to Sperm Figure 28 01 04.jpg
The process of spermatogenesis as the cells progress from primary spermatocytes, to secondary spermatocytes, to spermatids, to Sperm
Cycle of the seminiferous epithelium of the testis Seminiferous Cycle.svg
Cycle of the seminiferous epithelium of the testis

Spermatocytogenesis is the male form of gametocytogenesis and results in the formation of spermatocytes possessing half the normal complement of genetic material. In spermatocytogenesis, a diploid spermatogonium, which resides in the basal compartment of the seminiferous tubules, divides mitotically, producing two diploid intermediate cells called primary spermatocytes. Each primary spermatocyte then moves into the adluminal compartment of the seminiferous tubules and duplicates its DNA and subsequently undergoes meiosis I to produce two haploid secondary spermatocytes, which will later divide once more into haploid spermatids. This division implicates sources of genetic variation, such as random inclusion of either parental chromosomes, and chromosomal crossover that increases the genetic variability of the gamete. The DNA damage response (DDR) machinery plays an important role in spermatogenesis. The protein FMRP binds to meiotic chromosomes and regulates the dynamics of the DDR machinery during spermatogenesis. [13] FMRP appears to be necessary for the repair of DNA damage.

During spermatocytogenesis, meiosis employs special DNA repair processes that remove DNA damages and help maintain the integrity of the genome that is passed on to progeny. [14] These DNA repair processes include homologous recombinational repair and non-homologous end joining [14]

Each cell division from a spermatogonium to a spermatid is incomplete; the cells remain connected to one another by bridges of cytoplasm to allow synchronous development. Not all spermatogonia divide to produce spermatocytes; otherwise, the supply of spermatogonia would run out. Instead, spermatogonial stem cells divide mitotically to produce copies of themselves, ensuring a constant supply of spermatogonia to fuel spermatogenesis. [15]

Spermatidogenesis

Spermatidogenesis is the creation of spermatids from secondary spermatocytes. Secondary spermatocytes produced earlier rapidly enter meiosis II and divide to produce haploid spermatids. The brevity of this stage means that secondary spermatocytes are rarely seen in histological studies.

Spermiogenesis

During spermiogenesis, the spermatids begin to form a tail by growing microtubules on one of the centrioles, which turns into basal body. These microtubules form an axoneme. Later the centriole is modified in the process of centrosome reduction. [16] The anterior part of the tail (called midpiece) thickens because mitochondria are arranged around the axoneme to ensure energy supply. Spermatid DNA also undergoes packaging, becoming highly condensed. The DNA is packaged firstly with specific nuclear basic proteins, which are subsequently replaced with protamines during spermatid elongation. The resultant tightly packed chromatin is transcriptionally inactive. The Golgi apparatus surrounds the now condensed nucleus, becoming the acrosome.

Maturation then takes place under the influence of testosterone, which removes the remaining unnecessary cytoplasm and organelles. The excess cytoplasm, known as residual bodies, is phagocytosed by surrounding Sertoli cells in the testes. The resulting spermatozoa are now mature but lack motility. The mature spermatozoa are released from the protective Sertoli cells into the lumen of the seminiferous tubule in a process called spermiation.

The non-motile spermatozoa are transported to the epididymis in testicular fluid secreted by the Sertoli cells with the aid of peristaltic contraction. While in the epididymis the spermatozoa gain motility and become capable of fertilization. However, transport of the mature spermatozoa through the remainder of the male reproductive system is achieved via muscle contraction rather than the spermatozoon's recently acquired motility.

Role of Sertoli cells

Labelled diagram of the organisation of Sertoli cells (red) and spermatocytes (blue) in the testis. Spermatids which have not yet undergone spermiation are attached to the lumenal apex of the cell Germinal epithelium testicle.svg
Labelled diagram of the organisation of Sertoli cells (red) and spermatocytes (blue) in the testis. Spermatids which have not yet undergone spermiation are attached to the lumenal apex of the cell

At all stages of differentiation, the spermatogenic cells are in close contact with Sertoli cells which are thought to provide structural and metabolic support to the developing sperm cells. A single Sertoli cell extends from the basement membrane to the lumen of the seminiferous tubule, although the cytoplasmic processes are difficult to distinguish at the light microscopic level.

Sertoli cells serve a number of functions during spermatogenesis, they support the developing gametes in the following ways:

The intercellular adhesion molecules ICAM-1 and soluble ICAM-1 have antagonistic effects on the tight junctions forming the blood-testis barrier. [18] ICAM-2 molecules regulate spermatid adhesion on the apical side of the barrier (towards the lumen). [18]

Influencing factors

The process of spermatogenesis is highly sensitive to fluctuations in the environment, particularly hormones and temperature. Testosterone is required in large local concentrations to maintain the process, which is achieved via the binding of testosterone by androgen binding protein present in the seminiferous tubules. Testosterone is produced by interstitial cells, also known as Leydig cells, which reside adjacent to the seminiferous tubules.

Seminiferous epithelium is sensitive to elevated temperature in humans and some other species, and will be adversely affected by temperatures as high as normal body temperature. In addition, spermatogonia do not achieve maturity at body temperature in most of mammals, as β-polimerase and spermatogenic recombinase need a specific optimal temperature. [19] Consequently, the testes are located outside the body in a sac of skin called the scrotum. The optimal temperature is maintained at 2 °C (man) (8 °C mouse) below body temperature. This is achieved by regulation of blood flow [20] and positioning towards and away from the heat of the body by the cremasteric muscle and the dartos smooth muscle in the scrotum.

One important mechanism is a thermal exchange between testicular arterial and venous blood streams. Specialized anatomic arrangements consist of two zones of coiling along the internal spermatic artery. This anatomic arrangement prolongs the time of contact and the thermal exchange between the testicular arterial and venous blood streams and may, in part, explain the temperature gradient between aortic and testicular arterial blood reported in dogs and rams. Moreover, reduction in pulse pressure, occurring in the proximal one third of the coiled length of the internal spermatic artery.[ clarification needed ] [21] [22] Moreover, the activity of spermatogenic recombinase decreases, and this is supposed to be an important factor of testicles degeneration.[ clarification needed ] [23]

Dietary deficiencies (such as vitamins B, E and A), anabolic steroids, metals (cadmium and lead), x-ray exposure, dioxin, alcohol, and infectious diseases will also adversely affect the rate of spermatogenesis. [24] In addition, the male germ line is susceptible to DNA damage caused by oxidative stress, and this damage likely has a significant impact on fertilization and pregnancy. [25] According to the study by Omid Mehrpour et al exposure to pesticides also affects spermatogenesis. [26]

Hormonal control

Hormonal control of spermatogenesis varies among species. In humans the mechanism is not completely understood; however it is known that initiation of spermatogenesis occurs at puberty due to the interaction of the hypothalamus, pituitary gland and Leydig cells. If the pituitary gland is removed, spermatogenesis can still be initiated by follicle stimulating hormone (FSH) and testosterone. [27] In contrast to FSH, luteinizing hormone (LH) appears to have little role in spermatogenesis outside of inducing gonadal testosterone production. [27] [28]

FSH stimulates both the production of androgen binding protein (ABP) by Sertoli cells, and the formation of the blood-testis barrier. ABP is essential to concentrating testosterone in levels high enough to initiate and maintain spermatogenesis. Intratesticular testosterone levels are 20–100 or 50–200 times higher than the concentration found in blood, although there is variation over a 5- to 10-fold range amongst healthy men. [29] [30] Testosterone production does not remain constant throughout the day, but follows a circadian rhythm. The maximum peak of testosterone occurs at 8 a.m., which explains why men frequently suffer from morning erections. In younger men, testosterone peaks are higher. FSH may initiate the sequestering of testosterone in the testes, but once developed only testosterone is required to maintain spermatogenesis. [27] However, increasing the levels of FSH will increase the production of spermatozoa by preventing the apoptosis of type A spermatogonia. The hormone inhibin acts to decrease the levels of FSH. Studies from rodent models suggest that gonadotropins (both LH and FSH) support the process of spermatogenesis by suppressing the proapoptotic signals and therefore promote spermatogenic cell survival. [31]

The Sertoli cells themselves mediate parts of spermatogenesis through hormone production. They are capable of producing the hormones estradiol and inhibin. The Leydig cells are also capable of producing estradiol in addition to their main product testosterone. Estrogen has been found to be essential for spermatogenesis in animals. [32] [33] However, a man with estrogen insensitivity syndrome (a defective ERα) was found produce sperm with a normal sperm count, albeit abnormally low sperm viability; whether he was sterile or not is unclear. [34] Levels of estrogen that are too high can be detrimental to spermatogenesis due to suppression of gonadotropin secretion and by extension intratesticular testosterone production. [35] The connection between spermatogenesis and prolactin levels appears to be moderate, with optimal prolactin levels reflecting efficient sperm production. [28] [36]

Disorders

Disorders of spermatogenesis may cause oligospermia, which is semen with a low concentration of sperm [37] and is a common finding in male infertility.

See also

Related Research Articles

<span class="mw-page-title-main">Meiosis</span> Cell division producing haploid gametes

Meiosis (; from Ancient Greek μείωσις 'lessening', is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one copy of each chromosome. Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and a female will fuse to create a zygote, a cell with two copies of each chromosome again.

<span class="mw-page-title-main">Testicle</span> Internal organ in the male reproductive system

A testicle or testis is the male gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testicles are to produce both sperm and androgens, primarily testosterone. Testosterone release is controlled by the anterior pituitary luteinizing hormone, whereas sperm production is controlled both by the anterior pituitary follicle-stimulating hormone and gonadal testosterone.

<span class="mw-page-title-main">Gonad</span> Gland that produces sex cells

A gonad, sex gland, or reproductive gland is a mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sperm in the form of spermatozoa. The female gonad, the ovary, produces egg cells. Both of these gametes are haploid cells. Some hermaphroditic animals have a type of gonad called an ovotestis.

<span class="mw-page-title-main">Gametogenesis</span> Biological process

Gametogenesis is a biological process by which diploid or haploid precursor cells undergo cell division and differentiation to form mature haploid gametes. Depending on the biological life cycle of the organism, gametogenesis occurs by meiotic division of diploid gametocytes into various gametes, or by mitosis. For example, plants produce gametes through mitosis in gametophytes. The gametophytes grow from haploid spores after sporic meiosis. The existence of a multicellular, haploid phase in the life cycle between meiosis and gametogenesis is also referred to as alternation of generations.

<span class="mw-page-title-main">Germ cell</span> Gamete-producing cell

A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo meiosis, followed by cellular differentiation into mature gametes, either eggs or sperm. Unlike animals, plants do not have germ cells designated in early development. Instead, germ cells can arise from somatic cells in the adult, such as the floral meristem of flowering plants.

<span class="mw-page-title-main">Seminiferous tubule</span> Location of meiosis and creation of spermatozoa

Seminiferous tubules are located within the testicles, and are the specific location of meiosis, and the subsequent creation of male gametes, namely spermatozoa.

<span class="mw-page-title-main">Sertoli cell</span> Cells found in human testes which help produce sperm

Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis as a structural component of the seminiferous tubules. They are activated by follicle-stimulating hormone (FSH) secreted by the adenohypophysis and express FSH receptor on their membranes.

<span class="mw-page-title-main">Spermatid</span> Direct precursor of a sperm cell

The spermatid is the haploid male gametid that results from division of secondary spermatocytes. As a result of meiosis, each spermatid contains only half of the genetic material present in the original primary spermatocyte.

<span class="mw-page-title-main">Spermatocyte</span> Sperm precursor cell that undergoes meiosis

Spermatocytes are a type of male gametocyte in animals. They derive from immature germ cells called spermatogonia. They are found in the testis, in a structure known as the seminiferous tubules. There are two types of spermatocytes, primary and secondary spermatocytes. Primary and secondary spermatocytes are formed through the process of spermatocytogenesis.

Reproductive biology includes both sexual and asexual reproduction.

<span class="mw-page-title-main">Male reproductive system</span> Reproductive system of the human male

The male reproductive system consists of a number of sex organs that play a role in the process of human reproduction. These organs are located on the outside of the body, and within the pelvis.

<span class="mw-page-title-main">Human reproductive system</span> Organs involved in reproduction

The human reproductive system includes the male reproductive system, which functions to produce and deposit sperm, and the female reproductive system, which functions to produce egg cells and to protect and nourish the fetus until birth. Humans have a high level of sexual differentiation. In addition to differences in nearly every reproductive organ, there are numerous differences in typical secondary sex characteristics.

<span class="mw-page-title-main">Sperm</span> Male reproductive cell in anisogamous forms of sexual reproduction

Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction. Animals produce motile sperm with a tail known as a flagellum, which are known as spermatozoa, while some red algae and fungi produce non-motile sperm cells, known as spermatia. Flowering plants contain non-motile sperm inside pollen, while some more basal plants like ferns and some gymnosperms have motile sperm.

<span class="mw-page-title-main">Spermiogenesis</span> Final stage of spermatogenesis, involving spermatid maturation

Spermiogenesis is the final stage of spermatogenesis, during which the spermatids develop into mature spermatozoa. At the beginning of the stage, the spermatid is a more or less circular cell containing a nucleus, Golgi apparatus, centriole and mitochondria; by the end of the process, it has radically transformed into an elongated spermatozoon, complete with a head, midpiece, and tail.

<span class="mw-page-title-main">Blood–testis barrier</span> Physical barrier between the blood vessels and the seminiferous tubules of animal testes

The blood–testis barrier is a physical barrier between the blood vessels and the seminiferous tubules of the animal testes. The name "blood-testis barrier" is misleading as it is not a blood-organ barrier in a strict sense, but is formed between Sertoli cells of the seminiferous tubule and isolates the further developed stages of germ cells from the blood. A more correct term is the Sertoli cell barrier (SCB).

Spermatogenesis arrest is known as the interruption of germinal cells of specific cellular type, which elicits an altered spermatozoa formation. Spermatogenic arrest is usually due to genetic factors resulting in irreversible azoospermia. However some cases may be consecutive to hormonal, thermic, or toxic factors and may be reversible either spontaneously or after a specific treatment. Spermatogenic arrest results in either oligospermia or azoospermia in men. It is quite a difficult condition to proactively diagnose as it tends to affect those who have normal testicular volumes; a diagnosis can be made however through a testicular biopsy.

<span class="mw-page-title-main">Adjudin</span> Chemical compound

Adjudin (AF-2364) is a drug which is under development as a potential non-hormonal male contraceptive drug, which acts by blocking the production of sperm in the testes, but without affecting testosterone production. It is an analogue of the chemotherapy drug lonidamine, an indazole-carboxylic acid, and further studies continue to be conducted into this family of drugs as possible contraceptives.

<span class="mw-page-title-main">Sertoli cell-only syndrome</span> Medical condition

Sertoli cell-only syndrome (SCOS), also known as germ cell aplasia, is defined by azoospermia where the testicular seminiferous tubules are lined solely with sertoli cells. Sertoli cells contribute to the formation of the blood-testis barrier and aid in sperm generation. These cells respond to follicle-stimulating hormone, which is secreted by the hypothalamus and aids in spermatogenesis.

<span class="mw-page-title-main">Spermatogonial stem cell</span> Spermatogonium that does not differentiate into a spermatocyte

A spermatogonial stem cell (SSC), also known as a type A spermatogonium, is a spermatogonium that does not differentiate into a spermatocyte, a precursor of sperm cells. Instead, they continue dividing into other spermatogonia or remain dormant to maintain a reserve of spermatogonia. Type B spermatogonia, on the other hand, differentiate into spermatocytes, which in turn undergo meiosis to eventually form mature sperm cells.

In vitro spermatogenesis is the process of creating male gametes (spermatozoa) outside of the body in a culture system. The process could be useful for fertility preservation, infertility treatment and may further develop the understanding of spermatogenesis at the cellular and molecular level. 

References

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  30. ↑ Eberhard Nieschlag; Hermann M. Behre; Susan Nieschlag (26 July 2012). Testosterone: Action, Deficiency, Substitution. Cambridge University Press. pp. 130–. ISBN   978-1-107-01290-5..
  31. ↑ Pareek, Tej K.; Joshi, Ayesha R.; Sanyal, Amartya; Dighe, Rajan R. (2007). "Insights into male germ cell apoptosis due to depletion of gonadotropins caused by GnRH antagonists". Apoptosis. 12 (6): 1085–100. doi:10.1007/s10495-006-0039-3. PMID   17268770. S2CID   25378624.
  32. ↑ O'Donnell L, Robertson KM, Jones ME, Simpson ER (2001). "Estrogen and spermatogenesis". Endocr. Rev. 22 (3): 289–318. doi: 10.1210/edrv.22.3.0431 . PMID   11399746.
  33. ↑ Carreau S, Bouraima-Lelong H, Delalande C (2012). "Role of estrogens in spermatogenesis". Front Biosci. 4 (1): 1–11. doi: 10.2741/e356 . PMID   22201851.
  34. ↑ Smith, Eric P.; Boyd, Jeff; Frank, Graeme R.; Takahashi, Hiroyuki; Cohen, Robert M.; Specker, Bonny; Williams, Timothy C.; Lubahn, Dennis B.; Korach, Kenneth S. (1994). "Estrogen Resistance Caused by a Mutation in the Estrogen-Receptor Gene in a Man". New England Journal of Medicine. 331 (16): 1056–1061. doi: 10.1056/NEJM199410203311604 . ISSN   0028-4793. PMID   8090165.
  35. ↑ Edmund S. Sabanegh Jr. (20 October 2010). Male Infertility: Problems and Solutions. Springer Science & Business Media. pp. 83–. ISBN   978-1-60761-193-6.
  36. ↑ Spaggiari, Giorgia; Costantino, Francesco; Granata, Antonio R. M.; Tagliavini, Simonetta; Canu, Giulia; Varani, Manuela; De Santis, Maria Cristina; Roli, Laura; Trenti, Tommaso; Simoni, Manuela; Santi, Daniele (2023-08-01). "Prolactin and spermatogenesis: new lights on the interplay between prolactin and sperm parameters". Endocrine. 81 (2): 330–339. doi:10.1007/s12020-023-03375-x. ISSN   1559-0100. PMID   37140814. S2CID   258485662.
  37. ↑ thefreedictionary.com > oligospermia Citing: Dorland's Medical Dictionary for Health Consumers, 2007 by Saunders; The American Heritage Medical Dictionary 2007, 2004 by Houghton Mifflin Company; Mosby's Medical Dictionary, 8th edition 2009; McGraw-Hill Concise Dictionary of Modern Medicine, 2002 by The McGraw-Hill Companies

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